Significance of Trk-fused gene (TFG) in the pathogenesis of obesity and metabolic disorders

• Project/Area Number: 17K16150
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Hiroshima University
• Principal Investigator: Yamamotoya Takeshi 広島大学, 医系科学研究科(医), 助教 (50760013)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糖尿病 / 肥満 / 脂肪肝 / PPARγ / ミトコンドリア / 脂肪細胞 / 脂質代謝 / 細胞内小胞輸送 / 脂質

Outline of Final Research Achievements

We noticed that the abundance of Trk-fused gene (TFG) was drastically increased in white adipose tissues from ob/ob mice or HFD-fed mice. To elucidate the functions of adipocyte TFG in the pathogenesis of obesity, we generated tamoxifen-inducible mature adipocyte specific TFG knockout mice (AiTFG KO) and analyzed the phenotype. Upon high-fat diet feeding, AiTFG KO displayed impaired adipose expansion and worsening hepatic steatosis, leading to exacerbation of glucose intolerance. Downregulation of PPARγ expression and impairment of mitochondrial number and function in TFG depleted adipocytes were suggested as underlying mechanisms.

Academic Significance and Societal Importance of the Research Achievements

日本人は欧米人と比べ、軽度の肥満でも脂肪肝や耐糖能障害を呈することが知られている。過剰なエネルギー摂取に応答して脂肪組織が適切に肥大化することは異所性脂肪蓄積、それに伴うインスリン抵抗性の増大を防ぐために重要であり、脂肪組織TFGの発現増加がその一端を担っている可能性が本研究により示唆された。筋肉や肝臓など他の代謝標的臓器におけるTFGの機能について今後の検討が必要であるが、少なくともTFG発現を脂肪組織特異的に誘導することで、過剰エネルギーの脂肪組織への蓄積が促進され、脂肪肝の改善やインスリン抵抗性の改善が期待でき、糖尿病・脂肪肝の治療ターゲットとなる可能性が示された。

Research Products

• [Journal Article] Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells (2020)
  • Author(s): Nakatsu Yusuke、Yamamotoya Takeshi、Ueda Koji、Ono Hiraku、Inoue Masa-Ki、Matsunaga Yasuka、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Matsubara Akio、Asano Tomoichiro
  • Journal Title: Cancer Letters Volume: 470 Pages: 106-114
  • DOI: 10.1016/j.canlet.2019.10.043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins (2019)
  • Author(s): Inoue Masa-Ki、Nakatsu Yusuke、Yamamotoya Takeshi、Hasei Shun、Kanamoto Mayu、Naitou Miki、Matsunaga Yasuka、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Kushiyama Akifumi、Asano Tomoichiro
  • Journal Title: Cells Volume: 8 Issue: 12 Pages: 1545-1545
  • DOI: 10.3390/cells8121545
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice (2019)
  • Author(s): Mizuno Yu、Yamamotoya Takeshi、Nakatsu Yusuke、Ueda Koji、Matsunaga Yasuka、Inoue Masa-Ki、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Kikuchi Takako、Takahashi Masahiro、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Asano Tomoichiro、Kushiyama Akifumi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 19 Pages: 4680-4680
  • DOI: 10.3390/ijms20194680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice (2019)
  • Author(s): Inoue Masa-Ki、Matsunaga Yasuka、Nakatsu Yusuke、Yamamotoya Takeshi、Ueda Koji、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Iwashita Misaki、Sano Tomomi、Nishimura Fusanori、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Asano Tomoichiro
  • Journal Title: Diabetology & Metabolic Syndrome Volume: 11 Issue: 1 Pages: 57-57
  • DOI: 10.1186/s13098-019-0454-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
  • Journal Title: Cell Rep. Volume: 26 Issue: 12 Pages: 3221-3230
  • DOI: 10.1016/j.celrep.2019.02.066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation (2019)
  • Author(s): Ueda Koji、Nakatsu Yusuke、Yamamotoya Takeshi、Ono Hiraku、Inoue Yuki、Inoue Masa-Ki、Mizuno Yu、Matsunaga Yasuka、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Takahashi Shin-Ichiro、Matsubara Akio、Asano Tomoichiro
  • Journal Title: Oncotarget Volume: 10 Issue: 17 Pages: 1637-1648
  • DOI: 10.18632/oncotarget.26691
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective Effect of Sex Hormone-Binding Globulin against Metabolic Syndrome: In Vitro Evidence Showing Anti-Inflammatory and Lipolytic Effects on Adipocytes and Macrophages (2018)
  • Author(s): Yamazaki Hiroki、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Yamamotoya Takeshi、Nakatsu Yusuke、Kikuchi Takako、Kaneko Sunao、Tanaka Hirotoshi、Asano Tomoichiro
  • Journal Title: Mediators of Inflammation Volume: 2018 Pages: 1-12
  • DOI: 10.1155/2018/3062319
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of Gut-Derived Secretory Factors in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Their Possible Clinical Applications (2018)
  • Author(s): Okubo Hirofumi、Kushiyama Akifumi、Nakatsu Yusuke、Yamamotoya Takeshi、Matsunaga Yasuka、Fujishiro Midori、Sakoda Hideyuki、Ohno Haruya、Yoneda Masayasu、Asano Tomoichiro
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 10 Pages: 3064-3064
  • DOI: 10.3390/ijms19103064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of Pin1 inhibitors and their potential as therapeutic agents. (2018)
  • Author(s): Nakatsu Y, Matsunaga Y, Ueda K, Yamamotoya T, Inoue Y, Inoue MK, Mizuno Y, Kushiyama A, Ono H, Fujishiro M, Ito H, Okabe T, Asano T.
  • Journal Title: Curr Med Chem Volume: - Issue: 20 Pages: 1-1
  • DOI: 10.2174/0929867325666181105120911
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model (2018)
  • Author(s): Inoue Masa-Ki、Yamamotoya Takeshi、Nakatsu Yusuke、Ueda Koji、Inoue Yuki、Matsunaga Yasuka、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Suzuki Yusuke、Asano Tomoichiro、Kushiyama Akifumi
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 12 Pages: 3967-3967
  • DOI: 10.3390/ijms19123967
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gut microbiota as a therapeutic target for metabolic disorders. (2018)
  • Author(s): Okubo H, Nakatsu Y, Kushiyama A, Yamamotoya T, Matsunaga Y, Inoue MK, Fujishiro M, Sakoda H, Ohno H, Yoneda M, Ono H, Asano T.
  • Journal Title: Curr Med Chem. Volume: 25 Issue: 9 Pages: 984-1001
  • DOI: 10.2174/0929867324666171009121702
  • Peer Reviewed / Open Access
• [Journal Article] The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion (2017)
  • Author(s): Nakatsu Y, Mori K, Matsunaga Y, Yamamotoya T, Ueda K, Inoue Y, Mitsuzaki-Miyoshi K, Sakoda H, Fujishiro M, Yamaguchi S, Kushiyama A, Ono H, Ishihara H, Asano T.
  • Journal Title: J Biol Chem. Volume: 292 Issue: 28 Pages: 11886-11895
  • DOI: 10.1074/jbc.m117.780726
  • Peer Reviewed / Open Access
• [Journal Article] The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice. (2017)
  • Author(s): Yusuke Nakatsu, Hiroki Kokubo, Batmunkh Bumdelger, Masao Yoshizumi, Takeshi Yamamotoya, Yasuka Matsunaga, Koji Ueda, Yuki Inoue, Masa-Ki Inoue, Midori Fujishiro, Akifumi Kushiyama, Hiraku Ono, Hideyuki Sakoda, and Tomoichiro Asano
  • Journal Title: International Journal of Molecular Sciences Volume: 18(8) Issue: 8 Pages: 1704-1717
  • DOI: 10.3390/ijms18081704
  • Peer Reviewed / Open Access
• [Journal Article] Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity. (2017)
  • Author(s): Yamamotoya T, Nakatsu Y, Kushiyama A, Matsunaga Y, Ueda K, Inoue Y, Inoue MK, Sakoda H, Fujishiro M, Ono H, Kiyonari H, Ishihara H, Asano T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-017-13432-x
  • Peer Reviewed / Open Access
• [Journal Article] Gastrointestinal symptom prevalence depends on disease duration and gastrointestinal region in type 2 diabetes mellitus (2017)
  • Author(s): Fujishiro M, Kushiyama A, Yamazaki H, Kaneko S, Koketsu Y, Yamamotoya T, Kikuchi T, Sakoda H, Suzuki R, Kadowaki T
  • Journal Title: World J Gastroenterol Volume: 23 Issue: 36 Pages: 6694
  • DOI: 10.3748/wjg.v23.i36.6694
  • Peer Reviewed / Open Access
• [Presentation] Pin1 and Trk-fused gene (TFG): novel regulators for β-cell mass and function (2019)
  • Author(s): Takeshi Yamamotoya, Yusuke Nakatsu, Akifumi Kushiyama, Hisamitsu Ishihara, Tomoichiro Asano.
  • Organizer: 第62回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 脂肪細胞のTrk-fused gene (TFG) による代謝制御機構の解明 (2019)
  • Author(s): 山本屋 武、長谷井 竣、中津 祐介、井上 賢紀、迫田 秀之、藤城 緑、櫛山 暁史、浅野 知一郎
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] 脂肪細胞のTrk-fused gene (TFG) による代謝制御機構の解明 (2019)
  • Author(s): 山本屋 武、長谷井 竣、中津 祐介、井上 賢紀、櫛山 暁史、浅野 知一郎
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Trk-fused gene (TFG) の糖代謝調節における役割の解明 (2019)
  • Author(s): 山本屋 武，中津 祐介，上田 晃嗣，井上 賢紀，迫田 秀之， 藤城 緑，櫛山 暁史，石原 寿光，浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 脂肪細胞のTrk-fused gene (TFG) による代謝制御機構の解明 (2019)
  • Author(s): 山本屋 武、中津 祐介、上田 晃嗣、井上 賢紀、櫛山 暁史、浅野 知一郎
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Trk-fused gene (TFG) の膵β細胞における役割の解明 (2017)
  • Author(s): 山本屋 武，中津 祐介，松永 泰花，井上 由貴，迫田 秀之， 藤城 緑，山崎 広貴，菊池 貴子，櫛山 暁史，浅野 知一郎
  • Organizer: 第60回日本糖尿病学会年次学術集会